Adrenoceptors antagonists for the prevention and treatment of neurodegenerative conditions

ABSTRACT

The present disclosure teaches methods for treating and preventing a variety of neurodegenerative conditions and symptoms associated therewith, including Alzheimer&#39;s disease (AD) and idiopathic Parkinson&#39;s disease (iPD), by utilizing adrenoceptor antagonists. Adrenoceptor antagonists that can be used include β-blockers, such as acebutolol, betaxolol, bisopropolol, bopindolol, carvedilol, metoprolol, oxprenolol, propranolol, and timolol. The present disclosure also teaches methods for diagnosing and monitoring the progression of iPD.

CROSS REFERENCE TO RELATED APPLICATION

This application claims priority under 35 U.S.C. § 119(e) from U.S.Provisional Application No. 61/840,381 filed Jun. 27, 2013, which ishereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention generally relates to the prevention and treatmentof neurodegenerative conditions.

BACKGROUND

The following description includes information that may be useful inunderstanding the present invention. It is not an admission that any ofthe information provided herein is prior art or relevant to thepresently claimed invention.

Idiopathic Parkinson's disease (iPD) is a progressive disorder for whichthere is no known treatment capable of effectively slowing down orstopping disease progression. While symptomatic treatment of iPD ispossible, it is based mainly on dopaminergic supplementation, which onlytemporarily improves motor impairment and quality of life.

There is clearly a need for new treatments for iPD (and relatedneurodegenerative diseases) that alleviate the symptoms while alsoaddressing the underlying cause. There is also a need for methods ofdiagnosing iPD at an early stage, and monitoring its progression.

SUMMARY OF THE INVENTION

In various embodiments, the invention teaches a method for alleviatingthe symptoms of and/or slowing the progression of a neurodegenerativecondition in a subject. In some embodiments, the method includesproviding a therapeutically effective amount of a composition comprisingan adrenoceptor antagonist to the subject. In certain embodiments, theneurodegenerative condition is selected from the group consisting ofidiopathic Parkinson's disease (iPD), Dementia with Lewy Bodies (DLB),Multiple System Atrophy (MSA), Pure Autonomic Failure (PAF), Alzheimer'sdisease (AD), Progressive Supranuclear Palsy (PSP), Cortico-BasalDegeneration (CBD), and Huntington's Disease (HD). In some embodiments,the neurodegenerative condition is idiopathic Parkinson's disease (iPD).In some embodiments, the adrenoceptor antagonist is an antagonist of areceptor selected from the group consisting of: α1, α2, β1, β2, andcombinations thereof. In some embodiments, the adrenoceptor antagonistis a β-blocker. In some embodiments, the composition has L-type calciumchannel blocking activity. In some embodiments, the method includesproviding a therapeutically effective amount of an L-type calciumchannel blocker to the subject. In certain embodiments, the compositionused in the inventive method includes a drug selected from the groupconsisting of: acebutolol, betaxolol, bisopropolol, bopindolol,carvedilol, metoprolol, oxprenolol, propranolol, and timolol. In someembodiments, the method further includes providing a compositioncomprising a dopaminergic agent to the subject. In certain embodiments,the subject is a mammal. In some embodiments, the subject is a human. Incertain embodiments, one of the symptoms is constipation.

In various embodiments, the invention teaches a method for preventing aneurodegenerative condition in a subject, including providing aprophylactically effective amount of a composition including anadrenoceptor antagonist to the subject. In certain embodiments, theneurodegenerative condition is selected from the group consisting of:idiopathic Parkinson's disease (iPD), Dementia with Lewy Bodies (DLB),Multiple System Atrophy (MSA), Pure Autonomic Failure (PAF), Alzheimer'sdisease (AD), Progressive Supranuclear Palsy (PSP), Cortico-BasalDegeneration (CBD), and Huntington's Disease (HD). In certainembodiments, the neurodegenerative condition is idiopathic Parkinson'sdisease (iPD). In some embodiments, the adrenoceptor antagonist is anantagonist of a receptor selected from the group consisting of: α1, α2,β1, β2, and combinations thereof. In certain embodiments, theadrenoceptor antagonist is a β-blocker. In some embodiments, thecomposition includes a drug having L-type calcium channel blockingactivity. In some embodiments, the invention includes providing atherapeutically effective amount of an L-type calcium channel blocker tothe subject. In certain embodiments, the method includes providing adopaminergic agent to the subject. In some embodiments, the compositionused in the method includes a drug selected from the group consistingof: acebutolol, betaxolol, bisopropolol, bopindolol, carvedilol,metoprolol, oxprenolol, propranolol, and timolol. In some embodiments,the subject is a mammal. In certain embodiments, the subject is a human.

In various embodiments, the invention teaches a method for determiningwhether or not idiopathic Parkinson's disease (iPD) is progressing in asubject, including: (1) performing an initial assay to measure cardiacuptake of iodine-123-metaiodobenzylguanidine (¹²³I-MIBG) in a subjectsuspected of having, or having been diagnosed with, iPD; and (2)subsequently performing an additional assay to measure cardiac uptake of¹²³I-MIBG in the subject, wherein it is determined iPD is progressing inthe subject if the cardiac uptake of ¹²³I-MIBG has decreased in theadditional assay, compared to the initial assay; and wherein it isdetermined iPD is not progressing in the subject if the cardiac uptakeof ¹²³I-MIBG has not decreased in the additional assay, compared to theinitial assay. In some embodiments, the cardiac uptake of ¹²³I-MIBG ismeasured by ¹²³I-MIBG myocardial scintigraphy. In certain embodiments, acomposition including one or more adrenoceptor antagonist isadministered to the subject in the time between the initial andsubsequent assay, and the adrenoceptor antagonist is selected from thegroup consisting of: acebutolol, betaxolol, bisopropolol, bopindolol,carvedilol, metoprolol, oxprenolol, propranolol, and timolol.

In various embodiments, the invention teaches a method for diagnosing asubject with the presence or absence of idiopathic Parkinson's disease(iPD), including: performing an assay to measure cardiac uptake ofiodine-123-metaiodobenzylguanidine (¹²³I-MIBG) in a subject suspected ofhaving iPD, and diagnosing the subject as having iPD if the cardiacuptake of ¹²³I-MIBG is less than that of a subject who does not haveiPD, and diagnosing the subject as not having iPD, if the cardiac uptakeof ¹²³I-MIBG is not less than that of a subject who does not have iPD.In some embodiments, the cardiac uptake of ¹²³I-MIBG is measured by¹²³I-MIBG myocardial scintigraphy.

In various embodiments, the invention teaches a kit for preventing,treating, or slowing the progression of a neurodegenerative condition ina subject. In certain embodiments, the kit includes a compositionincluding an adrenoceptor antagonist; and instructions for the usethereof to prevent, treat, or slow the progression of aneurodegenerative condition. In certain embodiments, theneurodegenerative condition is selected from the group consisting ofidiopathic Parkinson's disease (iPD), Dementia with Lewy Bodies (DLB),Multiple System Atrophy (MSA), Pure Autonomic Failure (PAF), Alzheimer'sdisease (AD), Progressive Supranuclear Palsy (PSP), Cortico-BasalDegeneration (CBD), and Huntington's Disease (HD). In some embodiments,the neurodegenerative condition is idiopathic Parkinson's disease (iPD).In certain embodiments, the adrenoceptor antagonist is an antagonist ofa receptor selected from the group consisting of: α1, α2, β1, β2, andcombinations thereof. In certain embodiments, the adrenoceptorantagonist is a β-blocker. In some embodiments, the composition hasL-type calcium channel blocking activity. In some embodiments, the kitfurther includes an L-type calcium channel blocker. In certainembodiments, the composition includes a drug selected from the groupconsisting of: acebutolol, betaxolol, bisopropolol, bopindolol,carvedilol, metoprolol, oxprenolol, propranolol, and timolol. In someembodiments, the kit further includes a dopaminergic agent.

BRIEF DESCRIPTION OF THE DRAWINGS

Exemplary embodiments are illustrated in the referenced figures. It isintended that the embodiments and figures disclosed herein are to beconsidered illustrative rather than restrictive.

FIG. 1 demonstrates, in accordance with an embodiment of the invention,target organs of the sympathetic response to stress, mediated by thelocus coeruleus and sympathetic nervous system.

FIG. 2 demonstrates, in accordance with an embodiment of the invention,a diagram of the mechanism of abnormal α-synuclein accumulation mediatedby pathological activation of G-coupled receptor kinases (GRK) triggeredby norepinephrine (NE) overstimulation.

FIG. 3 demonstrates, in accordance with an embodiment of the invention,adrenergic receptor blockade slows down the pathological mechanismleading to α-synuclein accumulation and progression of the disease.

FIG. 4 demonstrates, in accordance with an embodiment of the invention,a graph indicating the influence of beta blocker treatment onconstipation in patients with Parkinson's disease.

DESCRIPTION OF THE INVENTION

All references cited herein are incorporated by reference in theirentirety as though fully set forth. Unless defined otherwise, technicaland scientific terms used herein have the same meaning as commonlyunderstood by one of ordinary skill in the art to which this inventionbelongs. March, Advanced Organic Chemistry Reactions, Mechanisms andStructure 5^(th) ed.; and Guyton and Hall, Textbook of MedicalPhysiology 12^(th) ed., provide one skilled in the art with a generalguide to many of the terms used in the present application.

One skilled in the art will recognize many methods and materials similaror equivalent to those described herein, which could be used in thepractice of the present invention. Indeed, the present invention is inno way limited to the methods and materials described. For purposes ofthe present invention, certain terms are defined below.

As used herein, “NE” is an acronym for norepinephrine.

As used herein, “E” is an abbreviation for epinephrine.

As used herein, “SNS” is an abbreviation for sympathetic nervous system.

As used herein, “iPD” is an acronym for idiopathic Parkinson's disease.

As used herein, “DLB” is an acronym for dementia with Lewy bodies.

As used herein, “MSA” is an acronym for multiple system atrophy.

As used herein, “PAF” is an acronym for pure autonomic failure.

As used herein, “AD” is an acronym for Alzheimer's disease.

As used herein, “PSP” is an acronym for progressive supranuclear palsy.

As used herein, “CBD” is an acronym for cortico-basal degeneration.

As used herein, “HD” is an acronym for Huntington's disease.

As used herein, “beneficial results” may include, but are in no waylimited to, lessening or alleviating the severity of a diseasecondition, or symptoms associated therewith, preventing a diseasecondition from worsening, curing a disease condition, preventing adisease condition from developing, lowering the chances of a subjectdeveloping a disease condition, and prolonging a subject's life or lifeexpectancy.

“Conditions,” “disease conditions,” and “neurodegenerative conditions,”as used herein, may include but are in no way limited to iPD, DLB, MSA,PAF, AD, PSP, CBD, and HD.

“Mammal,” as used herein, refers to any member of the class Mammalia,including, without limitation, humans and nonhuman primates such aschimpanzees and other apes and monkey species; farm animals such ascattle, sheep, pigs, goats and horses; domesticated mammals, such asdogs and cats; laboratory animals including rodents such as mice, ratsand guinea pigs, and the like. The term does not denote a particular ageor sex. Thus, adult and newborn subjects, whether male or female, areintended to be included within the scope of this term.

“Treatment” and “treating,” as used herein, refer to both therapeutictreatment and prophylactic or preventative measures, wherein the objectis to slow down (lessen) the neurodegenerative condition, prevent theneurodegenerative condition, pursue or obtain beneficial results, orlower the chances of the individual developing the neurodegenerativecondition, even if the treatment is ultimately unsuccessful. Those inneed of treatment include those already with the neurodegenerativecondition, as well as those prone to have the condition or those in whomthe condition is to be prevented.

In the embodiments described herein, in each instance in which the term“providing” is used with regard to the therapeutic compositions, theterm “administering” is also contemplated. In other words, in everyinstance in which a composition is provided, it could alternatively beadministered directly to the patient, and that is within the scope ofthe invention.

By way of background, β-adrenergic receptors are activated by NE andepinephrine (E). Cells in the central nervous system (CNS) which containE stimulate the activation of the SNS. Experimental observations inlaboratory animals revealed that the brain cells activating the SNScontain a substantial amount of neurotransmitter E, a neurotransmitterwhich potently activates β-adrenergic receptors.

Activation of the SNS increases alertness, attention, and energy, butexcessive activation induces symptoms that parallel the typicalpre-motor manifestations of iPD (constipation, sleep problems, anxiety,cardiac dysautonomia, anosmia, etc.). The inventors determined thatchronic adrenoceptor activation could sustain the progression ofdisease, increasing the rate of α-synuclein aggregation. The inventorsfurther determined that blockage of β-adrenergic receptors could relievethe clinical symptoms and reduce/revert the pathological mechanismleading to α-synuclein aggregation.

Motor symptoms could also improve with adrenoceptors modulation.Resting, postural, and action tremor in Parkinson's disease can bediminished by the β-adrenoceptor antagonist nadolol, and propranololcould reduce levodopa-induced dyskinesias without worseningParkinsonism. Levodopa-induced dyskinesias could also be diminished byadministration of α2-adrenergic receptor antagonists idaxozan andfipemazole, without a reduction in the anti-Parkinsonian benefits oflevodopa.

Importantly, β-blockers acting to reduce these symptoms need to enterinto the CNS by passage from the bloodstream across the blood-brainbarrier, and there block β-adrenergic receptors hyperactivation.β-blockers that have been demonstrated to pass the blood-brain barrier,and could therefore be useful in the inventive method, include, but arein no way limited to: acebutolol, betaxolol, bisopropolol, bopindolol,carvedilol, metoprolol, oxprenolol, propranolol, and timolol.

Advantageously, carvedilol has several different effects on theadrenoceptors, including β-1 and α-2 adrenergic blockade, α-1 adrenergicblockade, antioxidant activity, L-type calcium channel blockade, andinhibition of activation of stress-activated protein kinase. Therefore,carvedilol is particularly well-suited to block impaired sympatheticover-activation in early and advanced iPD. Absorption of current (oral)formulations of carvedilol is typically rapid and complete, with anaverage elimination half-life of about 8 hours. Carvedilol is ordinarilyremoved from the body in a two-part process, including liver and renalmechanisms. Some carvedilol liver metabolites could contribute to thebeneficial effects. For example, the antioxidant activity of thecarvedilol metabolite SB209995 has 50 to 100 times the potency ofcarvedilol and is 1000-fold more potent than vitamin E.

In view of all of the foregoing background and analysis, the inventorsestablished a novel strategy (described in greater detail below) totreat or prevent a number of neurodegerative disorders and symptomsassociated therewith.

In various embodiments, the invention teaches a method for preventing,slowing the progression of, or treating the symptoms of aneurodegenerative condition in a subject by providing a therapeuticallyeffective amount of a composition that includes one or more adrenoceptorantagonists to the subject. In some embodiments, two or more types ofadrenoceptor antagonists are provided separately. In some embodiments,the neurodegenerative condition is selected from the group consisting ofiPD, AD, and MSA. In some embodiments, the neurodegenerative conditionis any of the neurodegenerative conditions listed herein. In someembodiments, the composition includes a β1/β2- and/or α1/α2-receptorantagonist. In some embodiments, one or more of the adrenoceptorantagonists are β-blockers. In some embodiments, the adrenoceptorantagonists can include but are in no way limited to one or more of thefollowing: acebutolol, betaxolol, bisopropolol, bopindolol, carvedilol,metoprolol, oxprenolol, propranolol, timolol, and combinations thereof.In an embodiment, the adrenoceptor antagonist used in the inventivemethod is carvedilol. In a preferred embodiment, the neurodegenerativecondition is iPD, and at least one beta blocker is provided to thesubject. In a preferred embodiment, at least one of the beta-blockersprovided to the subject with iPD is carvedilol. One of skill in the artwould readily appreciate that racemic mixtures, optical isomers,analogs, derivatives, and salts of each of the aforementioned substancescould be used in the inventive methods. Furthermore, immediate-releaseas well as sustained-release preparations can be used with the inventivemethods.

In some embodiments, the therapeutic compositions described above areprovided in conjunction with, prior to, or after treatment withtraditional dopaminergic therapies, including those described in theexamples set forth herein. The compositions used in the inventivemethods described herein can be provided at each and every stage of theneurodegenerative diseases described herein. For example, one or moreadrenoceptor antagonists can be provided during any recognized stage ofiPD, including the very early stages described herein. Compositions usedin the inventive methods can also be provided prophylactically to anindividual believed to have an elevated risk of developing any of theconditions described herein, compared to an average individual. In someembodiments, the individual is a mammal. In some embodiments, theindividual is a human.

In various embodiments, one or more compounds or compositions describedherein may be provided as a pharmaceutical composition, including apharmaceutically acceptable excipient along with a therapeuticallyeffective amount of one or more of the compounds or compositionsdescribed herein. “Pharmaceutically acceptable excipient” means anexcipient that is useful in preparing a pharmaceutical composition thatis generally safe, non-toxic, and desirable, and includes excipientsthat are acceptable for veterinary use as well as for humanpharmaceutical use. Such excipients may be solid, liquid, semisolid, or,in the case of an aerosol composition, gaseous.

In various embodiments, the pharmaceutical compositions according to theinvention may be formulated for delivery via any route ofadministration. “Route of administration” may refer to anyadministration pathway known in the art, including but not limited toaerosol, nasal, oral, transmucosal, transdermal or parenteral.“Transdermal” administration may be accomplished using a topical creamor ointment or by means of a transdermal patch. “Parenteral” refers to aroute of administration that is generally associated with injection,including intraorbital, infusion, intraarterial, intracapsular,intracardiac, intradermal, intramuscular, intraperitoneal,intrapulmonary, intraspinal, intrasternal, intrathecal, intrauterine,intravenous, subarachnoid, subcapsular, subcutaneous, transmucosal, ortranstracheal. Via the parenteral route, the compositions may be in theform of solutions or suspensions for infusion or for injection, or aslyophilized powders. Via the enteral route, the pharmaceuticalcompositions can be in the form of tablets, gel capsules, sugar-coatedtablets, syrups, suspensions, solutions, powders, granules, emulsions,microspheres or nanospheres or lipid vesicles or polymer vesiclesallowing controlled release. Via the topical route, the pharmaceuticalcompositions based on compounds according to the invention may beformulated for treating the skin and mucous membranes and are in theform of ointments, creams, milks, salves, powders, impregnated pads,solutions, gels, sprays, lotions, suspensions, or other cosmeticproducts. They can also be in the form of microspheres or nanospheres orlipid vesicles or polymer vesicles or polymer patches and hydrogelsallowing controlled release. These topical-route compositions can beeither in anhydrous form or in aqueous form depending on the clinicalindication.

The pharmaceutical compositions used in the inventive methods can alsocontain any pharmaceutically acceptable carrier. “Pharmaceuticallyacceptable carrier” as used herein refers to a pharmaceuticallyacceptable material, composition, or vehicle that is involved incarrying or transporting one or more compositions or molecules ofinterest from one tissue, organ, or portion of the body to anothertissue, organ, or portion of the body. For example, the carrier may be aliquid or solid filler, diluent, excipient, solvent, or encapsulatingmaterial, or a combination thereof. Each component of the carrier mustbe “pharmaceutically acceptable” in that it must be compatible with theother ingredients of the formulation. It must also be suitable for usein contact with any tissues or organs with which it may come in contact,meaning that it must not carry a risk of toxicity, irritation, allergicresponse, immunogenicity, or any other complication that excessivelyoutweighs its therapeutic benefits.

In certain preferred embodiments, pharmaceutical compositions accordingto the invention can also be encapsulated, tableted or prepared in anemulsion or syrup for oral administration. Pharmaceutically acceptablesolid or liquid carriers may be added to enhance or stabilize thecomposition, or to facilitate preparation of the composition. Liquidcarriers include syrup, peanut oil, olive oil, glycerin, saline,alcohols and water. Solid carriers include starch, lactose, calciumsulfate, dihydrate, terra alba, magnesium stearate or stearic acid,talc, pectin, acacia, agar or gelatin. The carrier may also include asustained release material such as glyceryl monostearate or glyceryldistearate, alone or with a wax.

The pharmaceutical preparations are made following the conventionaltechniques of pharmacy involving milling, mixing, granulation, andcompressing, when necessary, for tablet forms; or milling, mixing andfilling for hard gelatin capsule forms. When a liquid carrier is used,the preparation will be in the form of syrup, elixir, emulsion or anaqueous or non-aqueous suspension. Such a liquid formulation may beadministered directly p.o. or filled into a soft gelatin capsule.

The pharmaceutical compositions according to the invention may bedelivered in a therapeutically effective amount. The precisetherapeutically effective amount is that amount of the composition thatwill yield the most effective results in terms of efficacy of treatmentin a given subject. This amount will vary depending upon a variety offactors, including but not limited to the characteristics of thetherapeutic composition (including activity, pharmacokinetics,pharmacodynamics, and bioavailability), the physiological condition ofthe subject (including age, sex, disease type and stage, generalphysical condition, responsiveness to a given dosage, and type ofmedication), the nature of the pharmaceutically acceptable carrier orcarriers in the formulation, and the route of administration. Oneskilled in the clinical and pharmacological arts will be able todetermine a therapeutically effective amount through routineexperimentation, for instance, by monitoring a subject's response toadministration of a composition or molecule and adjusting the dosageaccordingly. For additional guidance, see Remington: The Science andPractice of Pharmacy (Gennaro ed. 20th edition, Williams & Wilkins Pa.,USA) (2000).

Typical dosages of an effective amount of any of the adrenoceptorantagonists described herein can be as indicated to the skilled artisanby the in vitro responses or responses in animal models. Such dosagestypically can be reduced by up to about one order of magnitude inconcentration or amount without losing the relevant biological activity.Thus, the actual dosage will depend upon the judgment of the physician,the condition of the patient, and the effectiveness of the therapeuticmethod. The specific dosages and dosage ranges described herein beloware for the treatment and prevention of any of the neurodegenerativediseases described herein, including iPD.

In some embodiments, a therapeutic dosage range of acebutolol is between100 and 200 mg/70 kg every 10-12 h, when administered via the enteralroute to treat or prevent any neurodegenerative condition describedherein. In a preferred embodiment, the oral dosage of acebutolol neededto treat or prevent iPD motor and non-motor symptoms is 100 mg/70 kgevery 6 h.

In some embodiments, a therapeutic dosage range of betaxolol is between10 and 20 mg/70 kg every 10-12 h, when administered via the enteralroute to treat or prevent any neurodegenerative condition describedherein. In a preferred embodiment, the oral dosage of betaxolol neededto treat or prevent iPD motor and non-motor symptoms is 5 mg/70 kg every6 h.

In some embodiments, a therapeutic dosage range of bisopropolol isbetween 5 and 10 mg/70 kg every 10-12 h, when administered via theenteral route to treat or prevent any neurodegenerative conditiondescribed herein. In a preferred embodiment, the oral dosage ofbisoprolol needed to treat or prevent iPD motor and non-motor symptomsis 2.5 mg/70 kg every 6 h.

In some embodiments, a therapeutic dosage range of carvedilol is between12.5 and 25 mg/70 kg every 10-12 h, when administered via the enteralroute to treat or prevent any neurodegenerative condition describedherein. In a preferred embodiment, the oral dosage of carvedilol neededto treat or prevent iPD motor and non-motor symptoms is 6.25 mg/70 kgevery 6 h, or 10 mg/day using the controlled-release form.

In some embodiments, a therapeutic dosage range of metoprolol tartrateis between 100 and 200 mg/70 kg every 10-12 h, when administered via theenteral route to treat or prevent any neurodegenerative conditiondescribed herein. In a preferred embodiment, the oral dosage ofmetoprolol tartrate needed to treat or prevent iPD motor and non-motorsymptoms is 50 mg/70 kg every 6 h.

In some embodiments, a therapeutic dosage range of oxprenolol is between160 and 320 mg/70 kg every 10-12 h, when administered via the enteralroute to treat or prevent any neurodegenerative condition describedherein. In a preferred embodiment, the oral dosage of oxprenolol neededto treat or prevent iPD motor and non-motor symptoms is 80 mg/70 kgevery 6 h.

In some embodiments, a therapeutic dosage range of pindolol is between 5and 10 mg/70 kg every 10-12 h, when administered via the enteral routeto treat or prevent any neurodegenerative condition described herein. Ina preferred embodiment, the oral dosage of pindolol needed to treat orprevent iPD motor and non-motor symptoms is 2.5 mg/70 kg every 6 h.

In some embodiments, a therapeutic dosage range of propanolol is between60 and 80 mg/70 kg every 10-12 h, when administered via the enteralroute to treat or prevent any neurodegenerative condition describedherein. In a preferred embodiment, the oral dosage of propanolol neededto treat or prevent iPD motor and non-motor symptoms is 40 mg/70 kgevery 6 h.

In some embodiments, a therapeutic dosage range of timolol is between 10and 20 mg/70 kg every 10-12 h, when administered via the enteral routeto treat or prevent any neurodegenerative condition described herein. Ina preferred embodiment, the oral dosage of timolol needed to treat orprevent iPD motor and non-motor symptoms is 5 mg/70 kg every 6 h.

In some embodiments, a therapeutic dosing regimen of one or more betablockers for a subject with iPD is one which results in a resting heartrate of about 80 or fewer beats per minute. In some embodiments, atherapeutic dosage regimen for a subject with iPD is one which resultsin a resting heart rate of about fewer than 78 beats per minute, orfewer than 76 beats per minute, or fewer than 74 beats per minute, orfewer than 72 beats per minute, or fewer than 70 beats per minute, orfewer than 68 beats per minute, or fewer than 66 beats per minute.

In various embodiments, the invention teaches a method for determiningwhether or not iPD is progressing in a subject. In some embodiments, themethod includes (1) performing an initial assay to measure cardiacuptake of iodine-123-metaiodobenzylguanidine (¹²³I-MIBG) in a subjectsuspected of having or having been diagnosed with iPD; and (2)subsequently performing an additional assay to measure cardiac uptake of¹²³I-MIBG in the subject, wherein iPD is determined to be progressing inthe subject if the cardiac uptake of ¹²³I-MIBG has decreased in theadditional assay, compared to the initial assay; and wherein iPD isdetermined to not be progressing in the subject if the cardiac uptake of¹²³I-MIBG has not decreased in the additional assay, compared to theinitial assay. In some embodiments, the cardiac uptake of ¹²³I-MIBG isdetermined by ¹²³I-MIBG myocardial scintigraphy, as normally performedby one of skill in the art. Non-limiting examples of applicable methodsare described in Courbon et al. Movement Disorders Vol. 18, No. 8, 2003,pp. 890-897; Oka et al. J Neural Transm (2011) 118:1323-1327; andNavarro-Otano et al. Parkinsonism and Related Disorders 20 (2014)192-197. In certain embodiments, a composition comprising anadrenoceptor antagonist (including one or more beta-blocker describedherein) is administered to the subject in the time between the initialand subsequent assays. In various embodiments, the adrenoceptorantagonist can include, but is in no way limited to acebutolol,betaxolol, bisopropolol, bopindolol, carvedilol, metoprolol, oxprenolol,propranolol, and timolol.

In various embodiments, the invention teaches a method for diagnosingthe presence or absence of iPD in a subject suspected as having iPD. Insome embodiments, the method includes: performing an assay to measurecardiac uptake of ¹²³I-MIBG in a subject suspected of having iPD, anddiagnosing the subject as having iPD if the cardiac uptake of ¹²³I-MIBGis less than that of a subject who does not have iPD; and diagnosing thesubject as not having iPD, if the cardiac uptake of ¹²³I-MIBG is notless than that of a subject who does not have iPD. In some embodiments,the cardiac uptake of ¹²³I-MIBG is measured by ¹²³I-MIBG myocardialscintigraphy, as normally performed by one of skill in the art. In someembodiments, the subject is diagnosed with iPD if the measured cardiacuptake of ¹²³I-MIBG in the subject is about the same as that of asubject with iPD at any stage. In some embodiments, the subject isdiagnosed as having a particular stage of iPD known to be associatedwith the measured level of cardiac uptake of ¹²³I-MIBG.

The present invention also teaches a kit directed to one or more of:treating, inhibiting, promoting the prophylaxis of, alleviating thesymptoms of, and reducing the likelihood of neurodegenerative diseases(such as any of those described herein), in a mammal in need thereof.The kit is an assemblage of materials or components, including at leastone of the inventive compounds or compositions described herein. Thus,in some embodiments the kit contains a composition including one or moreadrenoceptor antagonists. In some embodiments, one or more of theadrenoceptor antagonists are β-blockers. In some embodiments, theadrenoceptor antagonists can include but are in no way limited to one ormore of the following: acebutolol, betaxolol, bisopropolol, carvedilol,metoprolol, oxprenolol, pindolol, propranolol, timolol, and combinationsthereof. In an embodiment, the adrenoceptor antagonist included in theinventive kit is carvedilol. One of skill in the art would readilyappreciate that racemic mixtures, optical isomers, analogs, derivatives,and salts of each of the aforementioned substances could be included inthe inventive kit. Furthermore, immediate-release and sustained-releasepreparations can be included in the inventive kit.

The exact nature of the components configured in the inventive kitdepends on its intended purpose. By way of non-limiting examples, someembodiments are configured for one or more purpose selected from:treating, inhibiting, promoting the prophylaxis of, alleviating thesymptoms of, and/or reducing the likelihood of one or moreneurodegenerative conditions described herein, including iPD. In oneembodiment, the kit is configured particularly for the purpose oftreating mammalian subjects. In another embodiment, the kit isconfigured particularly for the purpose of treating human subjects. Inanother embodiment, the kit is configured for treating adolescent,child, or infant human subjects. In further embodiments, the kit isconfigured for veterinary applications, treating subjects such as, butnot limited to, farm animals, domestic animals, and laboratory animals.

Instructions for use can be included in the kit. “Instructions for use”typically include a tangible expression describing the technique to beemployed in using the components of the kit to effect a desired outcome,such as treating, inhibiting, promoting the prophylaxis of, alleviatingthe symptoms of, and/or reducing the likelihood of, or inhibiting aneurodegenerative condition described herein, including iPD, using theappropriate compositions and methods described herein. Optionally, thekit also contains other useful components, such as, diluents, buffers,pharmaceutically acceptable carriers, syringes, catheters, applicators,pipetting or measuring tools, or other useful paraphernalia as will bereadily recognized by those of skill in the art.

The materials or components assembled in the kit can be provided to thepractitioner stored in any convenient and suitable ways that preservetheir operability and utility. For example the components can be indissolved, dehydrated, or lyophilized form; they can be provided atroom, refrigerated or frozen temperatures. The components are typicallycontained in suitable packaging material(s). As employed herein, thephrase “packaging material” refers to one or more physical structuresused to house the contents of the kit, such as inventive compositions,molecules and the like. The packaging material is constructed bywell-known methods, preferably to provide a sterile, contaminant-freeenvironment. As used herein, the term “package” refers to a suitablesolid matrix or material such as glass, plastic, paper, foil, and thelike, capable of holding the individual kit components. Thus, forexample, a package can be one or more glass vials or plastic containersused to contain suitable quantities of an inventive compositiondisclosed herein. The packaging material generally has an external labelwhich indicates the contents and/or purpose of the kit and/or itscomponents.

One skilled in the art will recognize many methods and materials similaror equivalent to those described herein, which could be used in thepractice of the present invention. Indeed, the present invention is inno way limited to the methods and materials described.

EXAMPLES Example 1 BACKGROUND

By way of additional background, iPD is a non-hereditary, chronic, andprogressive neurodegenerative disorder of unknown etiology,characterized by the presence of bradykinesia (slowness of movements)associated with tremor at rest and/or muscle rigidity. iPD is typicallyassociated with a significant loss of dopaminergic neurons in thesubstantia nigra pars compacta (SNpc). The SNpc provides dopaminergicinnervation to the striatum, a brain structure mainly involved in thecontrol of movements. It is estimated that the appearance of iPD motorsymptoms does not occur until 50-80% of the dopaminergic neurons arelost.

The prevalence of iPD is approximately 1% in individuals over 65 yearsold. It is estimated that iPD affects almost 1.5 million people in theUnited States alone. In addition to characteristic motor symptoms, iPDis characterized by a number of “non-motor” symptoms, which add to theoverall morbidity burden. Importantly, non-motor features may precedethe diagnosis of iPD, sometimes by several years. They include autonomic(gastrointestinal dysfunction, cardiovascular dysfunction withorthostatic hypotension, urinary and sexual dysfunction, andhyperhidrosis), sleep (impaired sleep initiation and maintenance, rapideye movement (REM) behavior disorder, and excessive daytime sleepiness),sensory (pain, hyposmia, and visual dysfunction), and/orneuropsychiatric disturbances (anhedonia, apathy, anxiety, depression,panic attacks, dementia, and psychosis).

It is important to consider that the above symptoms cannot be adequatelyexplained by nigral pathology and dopaminergic deficiency and aregenerally not responsive to dopaminergic supplementation. Otherextra-nigral dopamine unresponsive symptoms, occurring mostly in laterstages of this disease, comprise postural instability and gaitdisorders, dementia and psychotic manifestations, although in somepatients these last symptoms may also precede motor parkinsonism in DLB.

After reviewing extensive scientific literature, and considering theirown clinical experiences, the inventors concluded that unresponsivenessto dopaminergic supplementation suggests that a mechanism different thanprimary nigral degeneration and dopaminergic deficiency may lie beneaththe pathophysiology of the aforementioned symptoms. Specifically, asindicated above, the inventors concluded that a dysfunction of NE,another critical neurotransmitter circuitry in the nervous system, couldexplain most if not all the “non-motor” symptoms of the disease and playa critical role in the occurrence of the classical motors symptoms aswell. The inventors believe that prolonged hyperactivity of adrenergicreceptors, initially a physiological response to stress of variousnature, can lead to accumulation of α-synuclein in a first (reversible)stage, and eventually to neuronal death. Importantly, while iPD isclassically believed to be a disease of primary degeneration, based onthe historical bias in favor of neuropathology as the diagnostic “goldstandard,” the inventors conclude that for many years iPD is areversible process, testified by a multitude of non-motor symptomsrelated to the over activity of the noradrenergic system.

With all of these considerations in mind, the inventors determined thata subject could be evaluated for one or more of the above-listed earlyiPD symptoms, and if a diagnosis of early iPD is made, by using themethods of diagnosis described herein or otherwise, then the subjectcould be treated according to one or more of the inventive methodsdescribed herein.

Example 2 Current Treatment of Motor and Non-Motor Symptoms of iPD

As indicated above, despite all advances, iPD continues to be aprogressive disorder for which no interventions are available to modifydisease progression. Current treatment of iPD is only symptomatic andbased mainly on dopaminergic supplementation, which temporarily improvesmotor impairment and quality of life. In certain embodiments, each ofthe following traditional treatment strategies could be used inconjunction with one or more of the inventive methods.

Dopaminergic Supplementation

Three main classes of dopaminergic agents are considered as first-linesymptomatic therapies: monoamine oxidase B (MAO-B) inhibitors, dopamineagonists (DAs), and levodopa. MAO-B inhibitors (both rasagiline andselegiline) are a first line option for initial monotherapy in patientswith mild disability. Although there is a suggestion that MAO-Binhibitors might be neuroprotective, there is no unequivocal proof fordisease modification through either of the two available MAO-Binhibitors. DAs act directly upon dopamine receptors, mainly in thestriatum, and are considered more efficacious on the cardinal motorfeatures of iPD than MAO-B inhibitors, although a comparative trial hasnot been conducted. Non-ergolinic DAs (pramipexole, ropinirole,rotigotine and piribedil) are preferred among different DAs classes,because ergolinic DAs (cabergoline or pergolide) have shown pulmonaryand cardiac valvular fibrotic reactions. In many national andinternational guidelines, DAs are recommended as a first-line therapy,particularly for young patients, because of a lower potential of DAs toinduce motor complications (e.g. dyskinesias or response oscillations)as compared with levodopa. However, DAs efficacy on motor symptoms islower than levodopa and patients started on DAs monotherapy willeventually need add-on levodopa as the disease progresses and motorsymptoms become more severe. DAs are associated with more adverseeffects (e.g. nausea, headache, leg edema, hallucinations, daytimesomnolence and sleep attacks or orthostatic hypotension). Moreover, iPDpatients treated with long-term DAs usually develop additional symptoms(not related to natural iPD history) including compulsive gambling,buying, sexual behavior, or eating, and commonly defined impulse controldisorders. Historically, levodopa has been widely considered the mosteffective drug to treat the motor features of iPD and it is accepted asa first-line initial monotherapy in elderly patients in whom motorcomplication risk is generally low. Despite its efficacy, the risk ofdeveloping motor complications (which affect virtually all iPD patientsafter long term levodopa treatment) represents the principal reason toconsider alternative dopaminergic therapies as initial monotherapy iniPD. Long-term motor complications, however, indicate thatnondopaminergic systems are associated with the progression of thedisease and could be a good target for disease modifying treatment.

Non-Dopaminergic Agents

Non-dopaminergic therapies have a little or absent role in the currenttreatment guidelines. Non-motor symptoms are not only frequent, but alsooften under-reported by patients and caregivers. Further, as they arefrequently under-recognized by clinicians, they remain consequentlyunder-treated. Moreover, the treatment merely addresses single ormultiple symptoms (e.g. constipation, sleep disturbances, mooddisorders, and autonomic dysfunction) in the same way as non iPDpatients because they are considered “accidental” features associatedwith the fundamental movement disorder based on a dopaminergic deficit.

In summary, the previously unmet medical needs of iPD are: (a) unknowncause; (b) progressive worsening of all clinical features, includingmotor (tremor, bradykinesia, and rigidity) and non-motor (autonomicdysfunction, sleep disturbance, depression, fatigue, apathy, anxiety,and progressive cognitive decline) symptoms; (c) advanced motorcomplications, often associated with chronic dopaminergicsupplementation (involuntary movements such as dyskinesia or dystonia,balance impairment, postural disturbance, and unpredictable immobilitysuch as freezing of gait or prolonged “off” states); and (d) inadequatetremor control in many cases.

The inventors believe that some, if not all, of these unmet needs arerelated to the various roles of NE in the brain, and blocking ormodulating NE neurotransmission could improve the motor and non-motorproblems and protect against their progression in patients sufferingfrom or susceptible to developing iPD.

Example 3 Rationale for Therapeutic Approach

As indicated above, iPD is currently considered a progressiveneurodegenerative disease caused by the unexplained and premature deathof dopaminergic neurons in the substantia nigra pars compacta (SNc),which are classically found to accumulate abnormal protein aggregates,rich in α-synuclein and ubiquitin, called Lewy bodies. However, a numberof frequent, well-documented clinical and pathological features of iPDare not explained by the dopaminergic theory centered on thedegeneration of the SNc. Numerous non-motor symptoms, which are levodopaunresponsive and unrelated to dopaminergic mechanisms, frequently occurin iPD, often causing more disability than the classical (dopaminergic)motor symptoms. Importantly, several non-motor symptoms appear toprecede motor symptoms by many years, even up to two decades or more. Inaddition, Lewy bodies, the pathological marker of iPD, are notexclusively of the SNC, but have been found in many other cerebral andextra-cerebral locations, a finding that is considered by many expertsto be a marker of the progression of the disease. The mechanism offormation of Lewy bodies, the pathological marker of iPD, was previouslyunknown. In particular, it was unclear what led to the abnormalα-synuclein aggregates that characterize the neurons affected by thedisease. Finally, while the initial stages of the motor symptoms of iPDare responsive to dopaminergic supplementation (i.e. levodopa), thepre-motor symptoms and most importantly the symptoms marking theprogression of the disease (i.e. postural instability, cognitivedecline, motor fluctuations, and dyskinesias) are not affected bytreatment with dopaminergic drugs.

Other structures, in addition to the nigrostriatal system, are involvedin the neurodegenerative process that characterizes the progression ofiPD. Autopsy-based studies have confirmed that α-synuclein Lewypathology develops progressively in many nuclei and there is aparticular loss of NE neurons of the locus coeruleus (LC) in patientswith postmortem diagnosis of sporadic iPD, as well as in individualswith incidental (prodromal or premotor) Lewy body disease, but not inage and gender matched controls. Abnormal noradrenergic function in iPDcan be correlated with several of the non-motor symptoms, including:depression, REM-sleep disorder, and autonomic dysfunction. In fact, itappears that the contribution of the noradrenergic system in iPDdysfunction very likely explains many of the early non-motor symptoms ofthe disease.

Example 4 “Premotor” Parkinson's Disease

Most clinicians and researchers would agree on the likely existence ofthe premotor phase of iPD, based on clinical, pathologic, andepidemiologic studies. According to the so-called “Braak hypothesis,”there are six chronologically different iPD stages, based on theprogressive accumulation of Lewy bodies in the central nervous system.Synucleinopathic involvement of the SNc, considered the key event forthe occurrence of motor Parkinsonism, does not become evident untilstage 3. Extranigral loci, including the olfactory bulb, dorsal motornucleus of the vagus nerve, and the LC appear to be affected before theSNc. α-synuclein immunoreactivity with Lewy neuritis followed byconspicuous Lewy bodies is seen in the hypothalamus, as well as in thepre- and postganglionic sympathetic and parasympathetic structures, suchas in the enteric nervous system, cardiac and pelvic plexus, where thisprocess might even start according to some experts.

Abnormal α-synuclein aggregation and Lewy bodies' formation in autonomicand noradrenergic structures explain all typical non-motor symptoms ofiPD, and provide a mechanism to slow and potentially block theprogression of the disease at a very early stage, by using the inventivemethods.

Importantly, the current invention is partly based on the concept thatover activity—and not degeneration—of the noradrenergic system isresponsible for the early manifestations of iPD. The inventors believethat noradrenergic hyperactivity triggers non-motor symptoms and likelysustains progression of disease. Through the increased levels/activitiesof specific intracellular kinases, noradrenergic hyperactivity causesabnormal phosphorylation and aggregation of α-synuclein in alldopaminergic and non-dopaminergic efferent target neurons of the LC andthe SNS. In fact, all of the structures involved in the progressivestages of the “Braak hypothesis” are efferent targets of LC or SNS.

The pathophysiological link between SNS hyperactivity and thedevelopment and progression of PD is the excessive activation of beta-1adrenergic receptors in the target organs. In physiological conditions,G-coupled receptor kinases (GRKs) phosphorylate trans-membrane Greceptors (including the beta-1 adrenergic receptor) de-sensitizing anddown regulating them through the arrestin system, which ultimately leadsto a reduced membrane density. In pathological conditions, excessivereceptor stimulation induces a sharp increase of GRKs levels andactivity, which on one hand reduces beta-1 adrenergic receptor membranedensity, but on the other causes abnormal phosphorylation of alphasynuclein, which as a consequence aggregates forming the Lewy Bodies.Lewy Bodies typically start accumulating at the tip of the SNS axons(where the hyperactivity is maximal) and then spread antidromically tothe cell body, which will eventually degenerate. The inventors believeit would be advantageous to block adrenergic over activation in thepre-motor phase of the disease, in order to prevent pathologicalaccumulation of alpha-synuclein and the consequent development andprogression of iPD.

To confirm the important role of the noradrenergic system, an early andspecific extrastriatal sign of iPD is the impairment of the cardiacsympathetic system. The neuroimaging evidence for cardiac sympathetic“denervation” in iPD has been a watershed for the understanding of themechanisms that underlie early disease symptoms and progression.Decreased cardiac uptake of iodine-123-metaiodobenzylguanidine(¹²³I-MIBG), a physiological analog of NE, has been reported in patientswith iPD, and dementia with Lewy bodies (DLB). These imaging approachesare sensitive diagnostic tools that potentially differentiate iPD andDLB from other related disorders such as multiple system atrophy (MSA),progressive supranuclear palsy (PSP), corticobasal degeneration (CBD),Alzheimer's disease (AD) and parkin associated PD. In REM sleep behaviordisorder (RBD), a condition considered highly predictive of iPD,¹²³I-MIBG cardiac uptake is similar to iPD. One hypothesis about thedifference between the group of PD/DLB/RBD and other neurodegenerativediseases (MSA, PSP, CBD) is related to different kinds of gangliarneurodegeneration (post-in the first group and pre-in the second group).This finding suggests that cardiac sympathetic peripheral neurons mightbe affected in PD/DLB patients.

It is important to note, in support of the inventors' conclusions, thatsympathetic cardioneuropathy, as measured by ¹²³I-MIBG myocardialscintigraphy, is also characteristic of other common morbidities withrecognized pathophysiological correlation to SNS impairment, explainedas over-activity of the noradrenergic system. For example, a disparitybetween the neuronal release and the effective reuptake of NE in chronicheart failure (CHF) leads to an increased concentration of NE in thepresynaptic cleft, causing a down-regulation of the myocardialβ-adrenoceptors. In CHF patients, ¹²³I-MIBG myocardial scintigraphyshows a reduced cardiac reuptake similar to that observed in iPDpatients. The same scintigraphic results related to SNS hyperactivityare also commonly observed in hypertension, diabetes, and sleep apnea,which are all conditions significantly associated with iPD. In addition,patients with RBD show ¹²³I-MIBG myocardial scintigraphy impairment thatparallels iPD, and is explained as another example of neurodegeneration.However, patients with RBD and SA show lower ¹²³I-MIBG levels thanpatients with RBD without SA, suggesting a common mechanism.

Importantly, treatment with beta-blockers has improved ¹²³I-MIBGimpairment in CHF patients. The inventors believe that treatment withbeta-blockers could similarly improve cardiac dysautonomia in PDpatients. In addition to ¹²³I-MIBG myocardial scintigraphy, theinventors believe that beta-blockers will improve other cardiovasculardysautonomic symptoms, including orthostatic hypotension and heart ratevariability.

Example 5 Other Autonomic Dysfunctions in Parkinson's Disease: TheExample of Constipation

In addition to cardiovascular dysautonomia, other autonomic dysfunctionsare very common in patients with iPD, with a prevalence ranging from 14%to 80%. These symptoms further support the noradrenergic model, and caninclude gastrointestinal, urinary, sexual, and sudomotor dysfunction.

Constipation (less than three bowel movements per week) is the maingastrointestinal symptom seen in over 50% of iPD patients, precedingmotor symptoms by many years and at least doubling the risk of iPDdiagnosis. The enteric division of the autonomic nervous system islocated in the plexus of Auerbach and of Meissner, containingcholinergic and opioidergic ganglionic cells. These cells, bothsympathetically and parasympathetically innervated, and both sensitizedby intestinal filling, regulate intestinal mucous secretion andperistaltic transport. In Parkinson's disease, Lewy bodies andα-synuclein deposits are evidenced not only in the vagal nerve andsacral nuclei as well as the enteric nervous system, but also in centralparasympathetic structures (Barrington's defecation center).

Sensitized by intestinal filling, pressure waves are initiated byparasympathetic vagal (upper intestine) and pelvic (lower intestine)stimulation of the Auerbach's myenteric and Meissner's submucous plexus(facilitated by serotonin and inhibited by dopamine), and in the lowerintestine, these pressure waves are inhibited by the noradrenergicsympathetic hypogastric nerve. Therefore, noradrenergic hyperactivitywould explain the reduction of pressure waves, in particular aftereating, when food inside the gut should activate the gastrocolic reflex.

Barrington's defecation center is strictly related to the LC. TheLC-noradrenergic system is activated by visceral stimuli such as colonand bladder distension. Neurons of Barrington's nucleus (the pontinemicturition center) which project to both the LC and preganglioniccolumn of the lumbosacral spinal cord have been identified. The increasein LC discharge rate is often associated with activation of theforebrain electroencephalogram, indicating that the magnitude of LCactivation produced by these stimuli is sufficient to impact forebraintargets. LC activation by physiological stimuli may be important ininitiating a forebrain response that occurs in parallel with autonomicresponses to these physiological stimuli. In an animal model, colonicdistension increased the LC firing rate. In rats with lesions ofBarrington's nucleus caused by ibotenic acid, increasing LC activationby colonic distension was significantly reduced, confirming a pivotalrole of this nucleus in regulating brain noradrenergic systemhyperactivation.

In wild type (WT) rats, electrical stimulation (5-20 Hz) of the cervicalvagus elicited significant contractions in the mid colon and distalcolon, whereas less pronounced contractions were observed in theproximal colon. Parasympathetic pelvic nerve stimulation elicitedsignificant contractions in the rectum as well as the mid colon anddistal colon. A parasympathetic antagonist (atropine) abolished thecontractions induced by vagus nerve and pelvic nerve stimulation. On theother hand, sympathetic hypogastric nerve stimulation caused relaxationsin the rectum, mid colon and distal colon and beta-blocker (propanolol)abolished the relaxations induced by hypogastric nerve stimulation.

Currently, basic treatment of constipation in Parkinson's diseaseincludes dietary fiber, osmotic laxatives such as polyethylene glycol(PEG) (17 g/day) or lactulose (10-40 g/day), and psyllium preparations,in combination with physical exercise and adequate hydration.

Cholinomimetics (e.g. pyridostigmine bromide), peripheral dopamineantagonists (e.g. domperidone), 5-HT-4 receptor agonists (e.g. cisaprideor mosapride), and the prostaglandin misoprostol, are also reportedeffective to treat constipation, whereas dopaminomimetic drugs may behelpful in lower intestinal and anorectal function. As demonstratedherein, and especially in the ensuing examples, beta-blockers reducingnoradrenergic hyperactivity can improve gastrointestinal motordysfunction and reduce constipation in iPD patients.

Example 6 Data Regarding Constipation

The following case report of unexpected relief of bothersomeconstipation, abdominal bloating and pain by treatment with carvedilolin one Parkinson's disease patient, triggered the subsequent analysis ofpatient data reported herein.

Case Report

A pleasant 54 year old left-handed female presented with a 12-monthhistory of right hand tremors at rest associated with muscle pain of theright shoulder. Later on, she started dragging her right leg, trippingoccasionally. Diagnostic workup included a brain and C-spine MRI withnormal results. Voice, swallowing and handwriting were unaffected, buther ability to type with her right hand slowly deteriorated. Some ADLs,including dressing and blow drying her hair became progressively slowerand more clumsy. Her non-motor symptoms initially included hyposmia,“acting out dreams” and anxiety. At initial encounter, there was noconstipation, orthostatic dizziness, urinary frequency, sleepfragmentation, depression or cognitive decline. There was a history ofmild concussion 7 years before symptom onset but no exposure toneuroleptics. The patient grew up on a farm and was possibly exposed topesticides. The patient was initially started on dopamine agonist(pramipexole at doses up to 1.5 mg TID), which she tolerated well andpartially controlled her tremor. One year later, due to persistentbradykinesia and rigidity of her right side, a small dose of levodopa(Sinemet 25/100 TID) was added with almost complete resolution of motorsymptoms. During this time, she also developed constipation, sleepfragmentation and worsening anxiety. Low-dose beta-blocker therapy(carvedilol 6.25 mg BID) was started to treat anxiety avoiding thesedative effect of benzodiazepine. Her anxiety, constipation and sleepall improved dramatically. However, she self-discontinued carvedilolafter completing the first month of therapy because “she was taking toomany pills.” At next follow-up, she reported the return of bothersomeabdominal bloating and constipation. Carvedilol was restarted at thesame dose with virtually immediate resolution of GI symptoms.

Patient Data Analysis

The inventors conducted a retrospective, cross-sectional medical recordanalysis of 333 consecutive patients with a diagnosis of iPD seen in theMovement Disorders clinic of Cedars-Sinai Medical Center from October2010 to March 2014. Demographic and clinical data, including vitals,motor and non-motor symptoms, dopaminergic medications, comorbiditiesand anti-hypertensive medications were collected at the initialconsultation visit. All data were collected in an Excel database andanalyzed by SPSS version 19.0 (SPSS, Inc., Chicago, Ill.). Continuousvariables were expressed as mean±standard deviation and compared by theuse of Student t test (normally distributed) or as median±interquartilerange value and compared by the use of Mann-Whitney U test (not normallydistributed), as appropriate. Normality of data distribution wasevaluated using the Kolmogorov-Smirnov test. Categorical variables wereexpressed as proportion and compared by use of χ² test with risk ratiosand 95% confidence intervals quoted. To determine the independentpredictors of constipation, logistic regression analysis was performed.Variables achieving p<0.1 on univariate analysis were then included in amultivariate analysis. Statistical significance was accepted at p<0.05.

TABLE 1 Characteristics of Study Cohort Demographic and clinical dataAge, mean ± SD 68.5 ± 7.5  Gender male, n (%) 214 (64.3) PD duration,mean ± SD 7.4 ± 5.8 Tremor-like PD, n (%) 234 (70.3) PD treatmentLevodopa, n (%) 228 (68.5) Dopamine Agonists, n (%) 102 (30.6) MAO-I, n(%) 100 (30) Amantadine, n (%) 34 (10.2) Anticholinergics, n (%) 24(7.2) Other medications ACE-I/ARBs, n (%) 73 (21.9) Calcium ChannelBlockers, n (%) 28 (8.4) Beta-blockers, n (%) 63 (18.9) Diuretics, n (%)37 (11.1) Comorbidities pre-Hypertension, n (%) 108 (32.4) Hypertension,n (%) 128 (38.3) Diabetes Mellitus, n (%) 28 (8.4) Atrial fibrillation,n (%) 32 9.6)

Significantly, 203/327 patients (62.1%, 6 missing values) reportedconstipation, defined as the presence of constipation in the medicalrecords or the use of drugs to treat constipation or patient report ofinfrequent bowel movement, subjective complaint of straining atstooling, incomplete evacuation, and abdominal bloating. Constipationwas strongly associated with dopaminergic treatment. On the other hand,only 28/63 (44.4%) patients treated with beta-blockers reportedconstipation (Table 2).

TABLE 2 Reported Constipation in Cohort Constipation No Constipation pvalue Betablockers  28 (44.4%) 35 (55.6%) 0.002 No Betablockers 174(66.2%) 89 (33.8%)

TABLE 3 Logistic Regression Univariate and Multivariate Analyses 95% CIOR 95% CI OR β Wald OR Lower Upper p value β Wald OR Lower Upper p valueAge .032 8.575 1.033 1.011 1.056 .003 .035 8.038 1.035 1.011 1.060 .005Gender .078 .106 1.081 .677 1.724 .745 .117  .203 1.124  .677 1.865 .652PD duration .063 8.371 1.065 1.021 1.112 .004 .022  .782 1.023  .9731.075 .377 FHx .348 1.881 1.416 .861 2.327 .170 — — — — — — Tremor −.010.002 .990 .608 1.613 .968 — — — — — — Levodopa .978 15.984 2.659 1.6454.295 .0001 .731 5.775 2.077 1.144 3.769 .016 DA .637 5.868 1.891 1.1293.166 .015 .567 3.803 1.763 1.005 3.094 .048 MAO-IB −.292 1.385 .747.460 1.214 .239 — — — — — — Amantadine .424 1.154 1.528 .705 3.315 .283— — — — — — Anticholinergics .231 .264 1.260 .522 3.038 .607 — — — — — —ACE-I/ARBs −.410 2.296 .664 .391 1.128 .130 — — — — — — Beta-Blockers−.894 9.825 .409 .234 .715 .002 −1.121  13.194   .326  .178  .597  .0003Ca⁺⁺Antagonists −.541 1.863 .582 .268 1.266 .172 — — — — — — Diuretics−.176 .241 .838 .415 1.695 .624 — — — — — — Pre-HTN .086 .124 1.090 .6741.765 .725 — — — — — — HTN −.351 2.293 .704 .447 1.109 .130 — — — — — —DM .648 2.054 1.912 .786 4.640 .152 — — — — — — AF −.046 .014 .955 .4472.043 .906 — — — — — —

In a multivariate logistic analysis on constipation, including age,gender, PD duration, use of levodopa, use of dopamine-agonists and useof beta-blockers, the odds ratio of having constipation was 2.077(p=0.016) on levodopa and 1.763 (p=0.048) on dopamine agoniststreatment, but decreased to 0.326 (p=0.0003) in patients treated withbeta-blockers. None of the other anti-hypertensive drugs showed anycorrelation with the subjective report of constipation in this cohort.

TABLE 4 Constipation and Heart rate: Interaction with Dopaminergic DrugsNo Betablockers Betablockers No Constipation Constipation NoConstipation Constipation n % n % p value n % n % p value NoDopeminergic treatment 39 57.4% 29 42.6% <0.0001 12 85.7% 2 14.3% 0.027Levodopa only 32 28.3% 81 71.7% 14 40.0% 21 60.0% DA agonists only 420.0% 16 80.0% 1 50.0% 1 60.0% Levodopa + DA agonists 14 22.6% 48 77.4%8 66.7% 4 33.3%

TABLE 5 Constipation and Beta-blockers: Interaction with Heart Rate HR<80 bpm HR ≥80 bpm No Constipation Constipation p value No ConstipationConstipation p value No Betablockers 43 33.6% 85 66.4% .004 45 33.6% 8966.4% .153 Betablockers 27 57.4% 20 42.6% 8 50.0% 8 50.0%

Importantly, young age and treatments with beta-blockers were associatedwith a lower risk of constipation in this PD cohort, while dopaminergictreatments appeared to increase risk of constipation. Disease duration,corrected for age and pharmacological treatment, was not associated withincreased risk of constipation. As discussed above, intestinal motilityis regulated by the autonomic system and beta-blockers can positivelymodulate sympathetic input.

In reviewing the patient data, the inventors determined that in earlieriPD patients (approximately <5 years from iPD diagnosis) the diseaseseverity, as measured by the UPDRS part III in ON, was lower in patientstaking beta-blockers (10.29±4 versus 14.57±7 in patients without betablockers, p value=0.04).

Also, in patients with disease duration >5 years, the inventors foundthat beta-blockers are associated with less forgetfulness and apparentlyless overall “non-motor” burden.

Example 7 Conclusions

As demonstrated herein, beta-blockers reduce the overstimulation of thenoradrenergic system, and therefore can be used to improve autonomicdysfunction and associated non-motor symptoms in iPD patients, includingconstipation, bladder over-activity, sleep disorders, anxiety,hypertension, and others. In addition to providing symptomatic relief,beta-blockers could also slow the progression of the disease by reducingthe accumulation of α-synuclein/Lewy bodies induced by LC/SNShyperactivity. Reduced abnormal α-synuclein accumulation in Lewy bodieswill ultimately decrease the rate of neuronal death andneurodegeneration over time.

The various methods and techniques described above provide a number ofways to carry out the invention. Of course, it is to be understood thatnot necessarily all objectives or advantages described can be achievedin accordance with any particular embodiment described herein. Thus, forexample, those skilled in the art will recognize that the methods can beperformed in a manner that achieves or optimizes one advantage or groupof advantages as taught herein without necessarily achieving otherobjectives or advantages as taught or suggested herein. A variety ofalternatives are mentioned herein. It is to be understood that somepreferred embodiments specifically include one, another, or severalfeatures, while others specifically exclude one, another, or severalfeatures, while still others mitigate a particular feature by inclusionof one, another, or several advantageous features.

Furthermore, the skilled artisan will recognize the applicability ofvarious features from different embodiments. Similarly, the variouselements, features and steps discussed above, as well as other knownequivalents for each such element, feature or step, can be employed invarious combinations by one of ordinary skill in this art to performmethods in accordance with the principles described herein. Among thevarious elements, features, and steps some will be specifically includedand others specifically excluded in diverse embodiments.

Although the application has been disclosed in the context of certainembodiments and examples, it will be understood by those skilled in theart that the embodiments of the application extend beyond thespecifically disclosed embodiments to other alternative embodimentsand/or uses and modifications and equivalents thereof.

In some embodiments, the terms “a” and “an” and “the” and similarreferences used in the context of describing a particular embodiment ofthe application (especially in the context of certain of the followingclaims) can be construed to cover both the singular and the plural. Therecitation of ranges of values herein is merely intended to serve as ashorthand method of referring individually to each separate valuefalling within the range. Unless otherwise indicated herein, eachindividual value is incorporated into the specification as if it wereindividually recited herein. All methods described herein can beperformed in any suitable order unless otherwise indicated herein orotherwise clearly contradicted by context. The use of any and allexamples, or exemplary language (for example, “such as”) provided withrespect to certain embodiments herein is intended merely to betterilluminate the application and does not pose a limitation on the scopeof the application otherwise claimed. No language in the specificationshould be construed as indicating any non-claimed element essential tothe practice of the application.

Preferred embodiments of this application are described herein,including the best mode known to the inventors for carrying out theapplication. Variations on those preferred embodiments will becomeapparent to those of ordinary skill in the art upon reading theforegoing description. It is contemplated that skilled artisans canemploy such variations as appropriate, and the application can bepracticed otherwise than specifically described herein. Accordingly,many embodiments of this application include all modifications andequivalents of the subject matter recited in the claims appended heretoas permitted by applicable law. Moreover, any combination of theabove-described elements in all possible variations thereof isencompassed by the application unless otherwise indicated herein orotherwise clearly contradicted by context.

All patents, patent applications, publications of patent applications,and other material, such as articles, books, specifications,publications, documents, things, and/or the like, referenced herein arehereby incorporated herein by this reference in their entirety for allpurposes, excepting any prosecution file history associated with same,any of same that is inconsistent with or in conflict with the presentdocument, or any of same that may have a limiting affect as to thebroadest scope of the claims now or later associated with the presentdocument. By way of example, should there be any inconsistency orconflict between the description, definition, and/or the use of a termassociated with any of the incorporated material and that associatedwith the present document, the description, definition, and/or the useof the term in the present document shall prevail.

In closing, it is to be understood that the embodiments of theapplication disclosed herein are illustrative of the principles of theembodiments of the application. Other modifications that can be employedcan be within the scope of the application. Thus, by way of example, butnot of limitation, alternative configurations of the embodiments of theapplication can be utilized in accordance with the teachings herein.Accordingly, embodiments of the present application are not limited tothat precisely as shown and described.

1. A method for alleviating the symptoms of and/or slowing theprogression of a neurodegenerative condition in a subject, comprisingproviding a therapeutically effective amount of a composition comprisingan adrenoceptor antagonist to the subject.
 2. The method of claim 1,wherein the neurodegenerative condition is selected from the groupconsisting of idiopathic Parkinson's disease (iPD), Dementia with LewyBodies (DLB), Multiple System Atrophy (MSA), Pure Autonomic Failure(PAF), Alzheimer's disease (AD), Progressive Supranuclear Palsy (PSP),Cortico-Basal Degeneration (CBD), and Huntington's Disease (HD).
 3. Themethod of claim 2, wherein the neurodegenerative condition is idiopathicParkinson's disease (iPD).
 4. The method of claim 3, wherein theadrenoceptor antagonist is an antagonist of a receptor selected from thegroup consisting of: α1, α2, β1, β2, and combinations thereof.
 5. Themethod of claim 3, wherein the adrenoceptor antagonist is a β-blocker.6. The method of claim 3, wherein the composition has L-type calciumchannel blocking activity.
 7. The method of claim 3, further comprisingproviding a therapeutically effective amount of an L-type calciumchannel blocker to the subject.
 8. The method of claim 3, wherein thecomposition comprises a drug selected from the group consisting of:acebutolol, betaxolol, bisopropolol, bopindolol, carvedilol, metoprolol,oxprenolol, propranolol, and timolol.
 9. The method of claim 3, furthercomprising providing a composition comprising a dopaminergic agent tothe subject.
 10. (canceled)
 11. The method of claim 3, wherein thesubject is a human.
 12. The method of claim 3, wherein one of thesymptoms is constipation. 13-37. (canceled)
 38. The method of claim 1,wherein iPD is in the pre-motor symptom phase of iPD.
 39. The method ofclaim 38, wherein the subject has not been diagnosed with iPD based onmotor symptoms, and does not exhibit a motor symptom of iPD.
 40. Themethod of claim 38, wherein the subject has been diagnosed with iPDbefore the subject exhibits a motor symptom of iPD by a method,comprising: performing an assay to measure cardiac uptake ofiodine-123-metaiodobenzylguanidine (¹²³I-MIBG) in a subject; anddiagnosing the subject as having iPD if the cardiac uptake of ¹²³I-MIBGis less than that of a subject who does not have iPD.
 41. The method ofclaim 40, wherein the cardiac uptake of ¹²³I-MIBG is measured by¹²³I-MIBG myocardial scintigraphy.
 42. The method of claim 38, whereinthe non-motor symptom of iPD is autonomic dysfunction, sleep related,sensory related, a neuropsychiatric disturbance or a combinationthereof.
 43. The method of claim 42, wherein the autonomic dysfunctionis a gastrointestinal dysfunction, a cardiovascular dysfunction withorthostatic hypotension, urinary dysfunction, sexual dysfunction,hyperhidrosis or a combination thereof.
 44. The method of claim 43,wherein the gastrointestinal dysfunction is constipation.
 45. The methodof claim 42, wherein the sleep related symptom is impaired sleepinitiation and maintenance, rapid eye movement (REM) behavior disorder,excessive daytime sleepiness or a combination thereof.
 46. The method ofclaim 42, wherein the sensory related symptom is pain, hyposmia, visualdysfunction or a combination thereof.
 47. The method of claim 42,wherein the neuropsychiatric disturbance is anhedonia, apathy, anxiety,depression, panic attach, dementia, psychosis or a combination thereof.